Inhibition of Alcohol Consumption by Non-Opioid beta-Endorphin Peptides. The societal impact of addictive drugs is enormous. The cost of health problems due to alcohol alone, was estimated at over $150 billion in 1995 (63). Considerable research has been directed toward finding a pharmacological "magic bullet" for drug addiction but the results have been disappointing. Recently, naltrexone, an opioid receptor antagonist, was approved by the FDA but naltrexone's ability to reduce alcohol drinking and frank recidivism is not impressive. Hence, there is a definite need for new pharmacological strategies for treating addiction to alcohol and other drugs. The proposed research will test the hypothesis that a beta-Endorphin(1-31)-derived peptides, the non-opioid dipeptide, II-Endorphin(30-31) (Gly-GIn), inhibits alcohol intake. The peptide is synthesized in brain by post-translational processing from beta-Endorphin(1-31) and is released by a subpopulation of beta-Endorphin neurons. Gly-GIn exhibits opioid antagonist properties, albeit not by an opioid receptor antagonism mechanism. Gly-GIn acts through a distinct non-opioid binding site (unpublished data), whereas naltrexone is an antagonist binding at specific opioid receptor subtypes, mu and delta. The longer term objective of this research is thus to identify new prototype mechanisms for controlling drug and specifically alcohol induced reward or motivation. The proposed research has three specific objectives: (1) To test the hypothesis that Gly-GIn inhibits ethanol intake by methods of direct injection into the VTA, nucleus accumbens, or the central nucleus of the amygdala. (2) To test the hypothesis that Gly-GIn inhibits ethanol-induced rises in ECF or dialysate dopamine and beta-Endorphin in the nucleus accumbens, by dialysis experiments. (3) Using immunohistochemical markers, test the hypothesis that the non-opioid Gly-GIn acts at the cellular level to inhibit opioid modulation of mesolimbic dopaminergic release at the projection sites of arcuate II-Endorphin neurons to the nucleus accumbens, VTA, and the central amygdala.